Immune potentiation to improve neonatal and pediatric vaccines Abstract: Neonatal and infant immune responses are generally weak and biased against a Th1 response making these vulnerable populations susceptible to multiple infectious diseases. The majority of infant deaths occur in the first six months of life due to vaccine preventable bacterial or viral respiratory or diarrheal infectious diseases. Early immunization is required to protect infants but is limited by the immaturity of the immune system. Innate immunity is central to all immunity as it instructs adaptive immunity to subsequently generate immune memory. Methods to overcome the innate immune deficit at birth have been long sought. Although there are intrinsic defects in neonatal B and T cells, it has been shown by our group and others that in vitro addition of adult antigen presenting cells (APCs) can restore antigen specific B- and T cell activation/memory responses in neonates. In preliminary work for this application we have determined that the central defect in neonatal immune responses may reside in APC function. Based on our recent findings we hypothesize that identification of antigen-agonist-adjuvant combinations that will induce optimum neonatal DC activation and function will improve vaccine responsiveness that may pave the way for novel modifications resulting in effective neonatal and pediatric vaccination. We will focus on TLR agonist-adjuvant (MF59) combinations to stimulate neonatal APC cells and compare results to 5-year old children (before and after booster vaccinations) and to adults. In order to demonstrate immune potentiation by incorporation of stronger TLR agonist-MF59 combination in a vaccine perspective, we will compare immunogenicity of genetically detoxified acellular pertussis toxoid to a less immunogenic, chemically detoxified pertussis toxoid (currently widely used in DTaP or TDaP) in neonates, 5 year olds and adults. The findings of this project will represent major public health significance for neonatal/ infant vaccinations as well as improving booster vaccinations.